Cocaine abuse has become a major public health problem in recent years as more reinforcing forms of the drug have become available. Acute intoxication from cocaine is marked by convulsions and cardiac arrhythmias, and chronic cocaine use can be associated with increasing behavioral pathology and toxicity. The mechanisms underlying the reinforcing and toxic effects of cocaine are not fully understood, particularly since cocaine has dual actions as a potentiator of catecholaminergic systems; in particular, the dopamine system, and as a local anesthetic. Although dopaminergic antagonists have shown some success in blocking the reinforcing effects of cocaine in experimental animals, there is, at present, no pharmacological treatment that is efficacious and acceptable to patients. Carbamazepine is a major antiepileptic drug that has also been shown to be effective in the treatment of manic-depressive disorder. Recent studies in the Biological Psychiatry Branch have shown that chronic carbamazepine is extremely effective in preventing cocaine-induced seizures and deaths in rats.
Carbamazepine is an iminostilbene derivative that is used clinically to treat seizure disorders, trigeminal neuralgia, and, most recently, manicdepressive illness. Carbamazepine is very effective as an anticonvulsant in several experimental seizure paradigms including amygdala kindling, alcohol withdrawal, and maximal electroconvulsive shock, but is less effective on seizures induced by pentylenetetrazole and high-dose picrotoxin. The effectiveness of anticonvulsants has been shown to depend upon the stage of evolution of the seizure process. For example, carbamazepine suppresses completed amygdala-kindled seizures in rats, but is ineffective in preventing their development. While diazepam inhibits the early development and fully-kindled phases of amygdala kindling, it is not effective in the later phase of kindling when seizures occur spontaneously. Conversely, phenytoin shows the opposite profile on amygdala-kindled seizures--it is ineffective in early stages, but blocks spontaneous seizures.
Lidocaine is a local anesthetic that can be used to kindle seizures when given repeatedly in large, but initially subconvulsant, doses. This process has been called pharmacological kindling. Local anesthetic seizures resemble those produced by electrical kindling of the amygdala in that there is a prominent facial component, clonic jerking of the forepaws, and electroencephalographic evidence of seizure activity in the amygdala. In addition, the lidocaine seizures have been shown to increase glucose utilization in the amygdala, hippocampus, and perirhinal cortex. Cocaine is equipotent to lidocaine as a local anesthetic, but additionally has psychomotor stimulant properties that are thought to result from its ability to block catecholamine reuptake. Repeated administration of low to moderate doses of cocaine induces increased motor activation and stereotypy, a process called behavioral sensitization or reverse tolerance. This aspect of cocaine's effect appears closely related to its psychomotor stimulant properties, as similar behavioral changes are not seen with repeated lidocaine administration, but are observed with other psychomotor stimulants; e.g., amphetamine. Repeated administration of high doses of cocaine results in the progressive development of seizures which follow a time course akin to kindling.
In a study at the National Institute of Mental Health, it was found that chronic oral treatment with carbamazepine inhibited the development of lidocaine- and cocaine-kindled seizures in the rat. The carbamazepine diet produces combined blood levels of carbamazepine and its -10,11-epoxide that are similar to those achieved in humans treated with carbamazepine for affective, pain, or seizure disorders.